{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:20:04Z","timestamp":1785406804016,"version":"3.56.0"},"reference-count":63,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T00:00:00Z","timestamp":1777852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020581","name":"Fondazione AIRC","doi-asserted-by":"crossref","award":["IG 25833"],"award-info":[{"award-number":["IG 25833"]}],"id":[{"id":"10.13039\/100020581","id-type":"DOI","asserted-by":"crossref"}]},{"name":"MIUR PRIN 2022","award":["2022L332YR"],"award-info":[{"award-number":["2022L332YR"]}]},{"name":"Institute Pasteur Italy\u2014Fondazione Cenci Bolognetti"},{"DOI":"10.13039\/501100004271","name":"Sapienza University of Rome","doi-asserted-by":"publisher","award":["RG12117A61923A6F"],"award-info":[{"award-number":["RG12117A61923A6F"]}],"id":[{"id":"10.13039\/501100004271","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RG12117A61923A6F"],"award-info":[{"award-number":["RG12117A61923A6F"]}],"id":[{"id":"https:\/\/ror.org\/02be6w209","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009531","name":"Italian Institute of Technology","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100009531","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/042t93s57","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004710","name":"Fondazione Umberto Veronesi","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004710","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/041g7jm83","id-type":"ROR","asserted-by":"publisher"}]},{"name":"European Union funding\u2014NextGeneration EU","award":["B53C23002030006"],"award-info":[{"award-number":["B53C23002030006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nanomaterials"],"abstract":"<jats:p>Medulloblastoma (MB) is the most frequent brain malignancy in children, frequently driven by deregulated Sonic Hedgehog (SHH) signaling. We previously identified the antidiabetic drug phenformin (Phen) as a potent Gli1 inhibitor that suppresses SHH-subtype MB growth. Despite its efficacy, systemic administration of Phen is limited by its potential to induce lactic acidosis, primarily through the suppression of hepatic gluconeogenesis. Here, we provide proof-of-concept that phospholipid (liposomes) and non-phospholipid (niosomes) vesicles (&lt;200 nm) can be used to deliver phenformin selectively. Our results show that these vesicle-based delivery systems efficiently entrap Phen (around 50%) and release it into SHH MB cells, reducing proliferation and activating energy stress responses at higher doses. Furthermore, treated cells exhibit marked downregulation of SHH target genes Gli1 and Ptch1. In vivo, phenformin-loaded nanocarriers selectively increased drug accumulation in cerebellar tumors while minimizing systemic and hepatic exposure. Notably, niosomes demonstrated superior brain tumor targeting compared to free drug or liposome administration, as reflected by higher intratumoral concentrations of Phen compared to free drug or liposome administration. Consistent with this targeted delivery, we observed a substantial decline in intratumoral Gli1 and Ptch1 expression, confirming effective SHH pathway modulation. Together, these findings propose a promising nanotechnology-based method to improve phenformin therapeutic index in SHH MB by enhancing tumor specificity and reducing systemic toxicity.<\/jats:p>","DOI":"10.3390\/nano16090566","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T10:01:30Z","timestamp":1777975290000},"page":"566","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Brain-Targeted Delivery of Phenformin Using Phospholipid and Non-Phospholipid Vesicles for SHH Medulloblastoma"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9446-8752","authenticated-orcid":false,"given":"Laura","family":"Di Magno","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Rinaldi","sequence":"additional","affiliation":[{"name":"Department of Drug Chemistry and Technology, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3299-6214","authenticated-orcid":false,"given":"Luca","family":"Campea","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Della Rocca","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2405-1983","authenticated-orcid":false,"given":"Jacopo","family":"Forte","sequence":"additional","affiliation":[{"name":"Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5565-6444","authenticated-orcid":false,"given":"Eleonora","family":"D\u2019Intino","sequence":"additional","affiliation":[{"name":"Department of Drug Chemistry and Technology, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5925-0974","authenticated-orcid":false,"given":"Sara","family":"Cairoli","sequence":"additional","affiliation":[{"name":"Division of Metabolic Diseases and Drug Biology, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, Via Ferdinando Baldelli 38, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca Maria","family":"Goffredo","sequence":"additional","affiliation":[{"name":"Division of Metabolic Diseases and Drug Biology, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, Via Ferdinando Baldelli 38, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3968-3385","authenticated-orcid":false,"given":"Maria","family":"Carafa","sequence":"additional","affiliation":[{"name":"Department of Drug Chemistry and Technology, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6584-1869","authenticated-orcid":false,"given":"Elena","family":"Del Favero","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, Via Fratelli Cervi 93, 20054 Segrate, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2505-1766","authenticated-orcid":false,"given":"Carlotta","family":"Marianecci","sequence":"additional","affiliation":[{"name":"Department of Drug Chemistry and Technology, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6694-2613","authenticated-orcid":false,"given":"Gianluca","family":"Canettieri","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy"},{"name":"Institute Pasteur Italia, Fondazione Cenci-Bolognetti, Viale Regina Elena 291, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"i1","DOI":"10.1093\/neuonc\/noaf168","article-title":"CBTRUS Statistical Report: Pediatric Brain Tumor Foundation Childhood and Adolescent Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2017\u20132021","volume":"27","author":"Price","year":"2025","journal-title":"Neuro-Oncology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/s41388-024-02967-9","article-title":"Heterogeneity and Tumoral Origin of Medulloblastoma in the Single-Cell Era","volume":"43","author":"Sheng","year":"2024","journal-title":"Oncogene"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4833","DOI":"10.1007\/s00431-023-05189-5","article-title":"Posterior Fossa Tumors in Children: Current Insights","volume":"182","author":"Formentin","year":"2023","journal-title":"Eur. 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